Lycopene is a promising chemopreventiveagent for prostatecancer (CaP). However, the actual effects of this dietary antioxidant on prostatic tissue are poorly understood. The preclinical phase of CaP is characterized by a gradual progression from normal epithelium through high-grade prostatic intraepithelial neoplasia (HGPIN), which is very likely the precursor lesion for CaP. We propose to conduct a placebo-controlled randomized trial to investigate the effects, after 6 months, of lycopene supplements (30 mg/day) on molecular and cell morphology markers in core needle biopsy samples from men with documented HGPIN. Participants will be recruited from the Urology services at Northwestern Memorial Hospital and the Lakeside Veterans Administration Hospital. We propose to investigate the following specific aims: Specific Aim 1:Molecular markers in tissue. We will use conventional immunohistochemistry and computer-based image analysis to test the hypothesis that the lycopene supplements alter the expression of proteins marking the status of proliferation, differentiation, cell regulation and apoptosis in high-risk tissue. We have chosen and prioritized a panel of markers that are differentially expressed during precancerous progression. Specific Aim 2: Nuclear morphometry. We will use a computerized image analysis system designed for the chemoprevention setting to test the hypothesis that the antioxidants cause a favorable change in a nuclear morphometry index based on nuclear size, shape and chromatin texture. Specific Aim 3:Serum androgen levels. We hypothesize, based on post hoc results of a phase Ill antioxidant trial, that the intervention will reduce levels of testosterone (total and non-SHBG bound) and cx-androstanediol glucuronide. Specific Aim 4: Growth factors in prostatic fluid (EPF). In previous work, we developed assays for EGF, TGF-a and TGF-Beta 1 in EPF, and reported that low EGF and high TGF-f3 1 were associated with CaP. We hypothesize that treatment increases EGF and decreases TGF-Beta 1 in these-prostatic secretions. Specific Aim 5: DNA oxidation markers in blood. We hypothesize that treatment decreases the oxidized bases HMdU and 8-OHdG in lymphocytes, and increases HMdU auto-antibodies in serum detected by a novel ELISA method. Results of the proposed research will be useful for clarifying the mechanisms of action of lycopene in the prostate, for designing phase III trials, and, more generally, for determining the chemopreventive potential of this relatively non-toxic dietary compound.